Approximately 28 million Americans are estimated to suffer from migraine attacks, the majority of them women (20 million; Lipton et al. 2001 Headache 41(7): 646-657), making this one of the most prevalent disorders today, yet it has been reported that only a minority of sufferers are diagnosed and receive appropriate treatment (Silberstein et al., 2002 “Monograph: The State of Migraine: Prevention and Treatment” ACCESS Medical Group, Department of Continuing Medical Education, 3395 North Arlington Heights Road, Suit A, Arlington Heights, Ill. 600004-1566; Diamond 2001 Postgraduate Medicine 109(1): 49-60: “A fresh look at migraine therapy”; Morgan et al. “Migraine Headaches”, 1998, University of Wisconsin Hospitals and Clinics Authority, Madison, Wis., Department of Nursing UWH #5355<www.texaschildneurology.com/migraine %20Headaches.htm>).
Characterization of the Migraine Disorder
The disorder characterized as “migraine” is generally considered a form of headache. However, migraine is a neurological multifactorial syndrome, of which headache is only one of the many ways the disease manifests itself. Migraines are characterized by recurrent attacks of severe, pulsating and disabling headache, vomiting, photo- and phonofobia and malaise, all of which generally worsens with movement. In 20% of the patients additional transient focal neurological (aura) symptoms may occur. The attacks occur in two forms, migraine without aura (common migraine), which occurs in 75% of the patients and with aura (classic migraine), occur in about 30% of the migraineurs. Both types however are experienced in one third of the subjects (<http://en. wikipedia.org/wiki/Migraine>; U.S. Pat. No. 6,465,517).
While it is apparent that migraine and the disability associated with severe migraine symptoms are a public health problem, the exact causes and mechanisms are still widely debated, which hampers treatment and diagnosis of the disorder. However, generic factors might be involved in the disease. It has also been suggested that patients may suffer from a defect in ion channels and have a disturbed energy metabolism in brain and skeletal muscle. These above described features are not observed with ordinary headache such as for example tension headache (U.S. Pat. No. 6,465,517). Empirical evidence has also suggested links between hormone levels and migraine. Hormonal levels in menstruating women are also implicated in the incidence of migraine.
In addition, certain comorbidities have also been observed in migraine sufferers, where “comorbidity” refers to a greater-than-coincidental association of two or more conditions in the same person. Migraine has been associated with several neurologic and psychological disorders, including epilepsy, depression, anxiety disorders, stroke, bipolar disorder and impaired cognition. Other comorbidities include irritable bowel syndrome, asthma, and mitral valve prolapse (Diamond 2002). Migraine associate with auras seem to be particularly linked to a higher incidence of stroke.
The symptoms and their timing vary considerably among migraine suffers, and to a lesser extent from one migraine attack to the next. Symptoms may vary in severity and regularity of occurrence as well as duration. Migraine can accompany, in some cases, other types of headaches, for example, tension headaches. Migraine often runs in families and can start in adolescence, although some research indicates that it can start in early childhood or even in utero. Silberstein et al., 2002 “Monograph: The State of Migraine: Prevention and Treatment” ACCESS Medical Group, Department of Continuing Medical Education, 3395 North Arlington Heights Road, Suit A, Arlington Heights, Ill. 600004-1566; Diamond 2001 Postgraduate Medicine 109(1): 49-60: “A fresh look at migraine therapy”; Morgan et al. “Migraine Headaches”, 1998, University of Wisconsin Hospitals and Clinics Authority, Madison, Wis., Department of Nursing UWH #5355<www.texaschildneurology.com/migraine %20Headaches.htm>; <http://en.wikipedia.org/wiki/Migraine>; U.S. Pat. No. 6,465,517).
Current Treatments
There are numerous regimens of suggested treatment for migraine and the symptoms which are part of the migraine disorder. However, to date, there does not appear to be a single treatment (including prevention or prophylaxis) that is successful for the majority of migraine sufferers. Additionally, treatment that has proven effective in a particular migraine sufferer may not continue to be successful, or may only be intermitently effective. The current standard of care for migraines focuses on three major areas: preventive drugs; avoidance of migraine triggers (e.g., particular foods, alcohol or other substances (e.g., paints, perfumes, etc.), exposure to certain environmental factors, and changes in sleep or lifestyle patterns, etc.); and/or drugs which treat migraine or the symptoms thereof once a migraine has developed (e.g., sumitriptan, analgesics, narcotic medications, antipsychotic drugs, anti-emetics (e.g., compazine). Treatment during migraine is often either ineffective, only partially effective or the therapeutica agents are associated with significant undesirable side effects, including one or more of: hypotension, tiredness, increased weight, breathlessness, dizziness, heaviness or pressure on the chest and arms, shortness of breath, chest pain, nausea, muscle cramps, or peripheral vasoconstriction; depending on the therapy of choice.
Imitrex® (sumitriptan) and related 5-hydroxytryptamine (serotonin) receptor agonists are now available and are often considered the therapy of choice for severe migraine that is relatively infrequent. These serotonin receptor agonists are effective and generally have few side effects when used occasionally. Side effects usually consist of dizziness, heaviness or pressure on the chest and arms, shortness of breath, and sometimes chest pain. Triptans are contra-indicated for patients with coronary artery disease. Some members of this family of drugs are: sumatriptan, zolmitriptan, naratriptan, rizatriptan, elitriptan. (http://en.wikipedia.org/wiki/Migraine>; U.S. Pat. Nos. 6,465,517; 6,255,334; 5,872,145; 5,721,252.)
As described above and known to those of skill in the art, a number of different therapies are available which may prevent or alleviate migraine some of the time for some individuals, but complete avoidance of the disease seems to be impossible and most of the prescribed drugs are known for their undesired side-effects. Certain beta-adrenoreceptor antagonists (propranolol, metoprolol, atenolol) have been described as efficacious for prevention or prophylaxis. However, beta-blockers have multiple side effects, like hypotension, tiredness, increased weight and breathlessness. For a number of years ergotamine or other ergot alkaloids were the only drugs for the treatment of migraine. (See for example U.S. Pat. No. 6,685,951.) However, they have low oral and rectal bioavailablity and may cause nausea, muscle cramps, or peripheral vasoconstriction. Further, calcium channel blockers, hormonal manipulators, analgesics, and non-steroidal anti-inflammatory drugs (NSAID's) are sometimes prescribed, but evidence for preventive efficacy is rare. Numerous patents and references are available detailing the current standard of care for migraine. See for example: U.S. Pat. Nos. 6,479,551; 6,716,837; 6,635,639, 6,476,042; 6,402,678; 6,077,539; 6,380,242, 6,255,334; 6,503,884; 6,251,935; 4,443,464; 5,744,4872; 5,036,078, 5,538,959; U.S. Pat. App. No. 2003/0008892 A1 and references cited therein.
Given the prevalence of the disorder and the related adverse effects on quality of life, productivity and medical costs, migraine has been characterized as a public health crisis (Silberstein et al., 2002, and references cited therein). In the American Migraine Study II (Lipton et al. 2001 Headache 41(7): 646-657), results were reported indicating that the highest incidence of migraine in women, the majority of sufferers, occurs between the ages of 25 and 55, the most productive years for the average working adult. Further, an increase in both severity and frequency of attacks was observed for women in their 30s. These statistics, along with the characteristics of migraine as a disorder—painful, debilitating and resulting in the loss of productivity in the workplace and participation with friends and family—highlights the need for effective therapies for a broad range of individuals. To date, there does not appear to be a drug or regimen which can effectively treat a broad range of those suffering from the pain and unpredictability associated with migraine. As is apparent from the studies quoted above, and any of the publicly available materials regarding migraines, e.g., public health (e.g., <www.headaches.org>), university, “self-help” websites, medical journals and continuing medical education monographs, there is an urgent need for effective drugs and treatment regimes to manage this disorder. (Silberstein et al., 2002 “Monograph: The State of Migraine: Prevention and Treatment” ACCESS Medical Group, Department of Continuing Medical Education, 3395 North Arlington Heights Road, Suit A, Arlington Heights, Ill. 600004-1566; Diamond 2001 Postgraduate Medicine 109(1): 49-60: “A fresh look at migraine therapy”; Morgan et al. “Migraine Headaches”, 1998, University of Wisconsin Hospitals and Clinics Authority, Madison, Wis., Department of Nursing UWH #5355<www.texaschildneurology.com/migraine %20Headaches.htm>; <http://en.wikipedia.org/wiki/Migraine>; U.S. Pat. Nos. 6,465,517; 6,479,551; 6,716,837; 6,635,639, 6,476,042; 6,402,678; 6,077,539; 6,380,242, 6,255,334; 6,503,884; 6,251,935; 4,443,464).
All references, patent, and patent applications cited herein are hereby incorporated by reference in their entirety.